The present invention relates to novel hexanoic acid derivatives, methods of use and pharmaceutical compositions containing them.
The compounds of the invention are useful in the preparation and use of compounds of formula 1, which are potent and selective inhibitors of MIP-1xcex1 binding to its receptor CCR1 found on inflammatory and immunomodulatory cells (preferably leukocytes and lymphocytes). The CCR1 receptor is also sometimes referred to as the CC-CKR1 receptor. The compounds of formula I also inhibit MIP-1xcex1 (and the related chemokines shown to interact with CCR1 (e.g., RANTES and MCP-3)) induced chemotaxis of THP-1 cells and human leukocytes and are potentially useful for the treatment or prevention of autoimmune diseases (such as rheumatoid arthritis, type I diabetes (recent onset), inflammatory bowel disease, optic neuritis, psoriasis, multiple sclerosis, polymyalgia rheumatica, uveitis, and vasculitis), acute and chronic inflammatory conditions (such as osteoarthritis, adult Respiratory Distress Syndrome, Respiratory Distress Syndrome of infancy, ischemia reperfusion injury, and glomerulonephritis), allergic conditions (such as asthma and atopic dermatitis), infection associated with inflammation (such as viral inflammation (including influenza and hepatitis) and Guillian-Barre), chronic bronchitis, xeno-transplantation, transplantation tissue rejection (chronic and acute), organ rejection (chronic and acute), atherosclerosis, restenosis, HIV infectivity (co-receptor usage), and granulomatous diseases (including sarcoidosis, leprosy and tuberculosis).
MIP-1xcex1 and RANTES are soluble chemotactic peptides (chemokines) which are produced by inflammatory cells, in particular CD8+ lymphocytes, polymorphonuclear leukocytes (PMNs) and macrophages, J.Biol. Chem., 270 (30) 29671-29675 (1995). These chemokines act by inducing the migration and activation of key inflammatory and immunomodulatory cells. Elevated levels of chemokines have been found in the synovial fluid of rheumatoid arthritis patients, chronic and rejecting tissue transplant patients and in the nasal secretions of allergic rhinitis patients following allergen exposure (Teran, et al., J. Immunol., 1806-1812 (1996), and Kuna et al., J. Allergy Clin. Immunol. 321 (1994)). Antibodies which interfere with the chemokine/receptor interaction by neutralizing MIP1xcex1 or gene disruption have provided direct evidence for the role of MIP-1 and RANTES in disease by limiting the recruitment of monocytes and CD8+lymphocytes (Smith et al., J. Immunol, 153, 4704 (1994) and Cook et al., Science, 269, 1583 (1995)). Together this data demonstrates that CCR1 antagonists would be an effective at treatment of several immune based diseases.
The present invention relates to compounds of the formula XXXI 
or the pharmaceutically acceptable salt thereof; wherein
R1 is quinoxalinyl optionally substituted with one or more substituents independently selected from the group consisting of hydrogen, deuterium, halo, CN, (C1-C6)alkyl optionally substituted with one or more fluorine atoms, hydroxy, hydroxy-(C1-C6)alkyl, (C1-C6)alkoxy optionally substituted with one or more fluorine atoms, (C1-C6)alkoxy(C1-C6)alkyl, HOxe2x80x94(Cxe2x95x90O)xe2x80x94, (C1-C6)alkyl-Oxe2x80x94(Cxe2x95x90O)xe2x80x94, HOxe2x80x94(Cxe2x95x90O)xe2x80x94(C1-C6)alkyl, (C1-C6)alkyl-Oxe2x80x94(Cxe2x95x90O)xe2x80x94(C1-C6)alkyl, (C1-C6)alkyl-(Cxe2x95x90O)xe2x80x94Oxe2x80x94, (C1-C6)alkyl-(Cxe2x95x90O)xe2x80x94Oxe2x80x94(C1-C6)alkyl, H(Oxe2x95x90C)xe2x80x94, H(Oxe2x95x90C)xe2x80x94(C1-C6)alkyl, (C1-C6)alkyl(Oxe2x95x90C)xe2x80x94, (C1-C6)alkyl(Oxe2x95x90C)xe2x80x94(C1-C6)alkyl, NO2, amino, (C1-C6)alkylamino, [(C1-C6)alkyl]2amino, amino(C1-C6)alkyl, (C1-C6)alkylamino(C1-C6)alkyl, [(C1-C6)alkyl]2amino(C1-C6)alkyl, H2Nxe2x80x94(Cxe2x95x90O)xe2x80x94, (C1-C6)alkyl-NHxe2x80x94(Cxe2x95x90O)xe2x80x94, [(C1-C6)alkyl]2Nxe2x80x94(Cxe2x95x90O)xe2x80x94, H2N(Cxe2x95x90O)xe2x80x94(C1-C6)alkyl, (C1-C6)alkyl-HN(Cxe2x95x90O)xe2x80x94(C1-C6)alkyl, [(C1-C6)alkyl]2Nxe2x80x94(Cxe2x95x90O)xe2x80x94(C1-C6)alkyl, H(Oxe2x95x90C)xe2x80x94NHxe2x80x94, (C1-C6)alkyl(Cxe2x95x90O)xe2x80x94NH, (C1-C6)alkyl(Cxe2x95x90O)xe2x80x94[NH](C1-C6)alkyl, (C1-C6)alkyl(Cxe2x95x90O)xe2x80x94[N(C1-C6)alkyl](C1-C6)alkyl, (C1-C6)alkyl-Sxe2x80x94, (C1-C6)alkyl-(Sxe2x95x90O)xe2x80x94, (C1-C6)alkyl-SO2xe2x80x94, (C1-C6)alkyl-SO2xe2x80x94NHxe2x80x94, H2Nxe2x80x94SO2xe2x80x94, H2Nxe2x80x94SO2xe2x80x94(C1-C6)alkyl, (C1-C6)alkylHNxe2x80x94SO2xe2x80x94(C1-C6)alkyl, [(C1-C6)alkyl]2Nxe2x80x94SO2xe2x80x94(C1-C6)alkyl, CF3SO3xe2x80x94, (C1-C6)alkyl-SO3xe2x80x94, phenyl, (C3-C10)cycloalkyl, (C2-C9)heterocycloalkyl, and (C2-C9)heteroaryl;
R2 is phenyl-(CH2)mxe2x80x94, naphthyl-(CH2)mxe2x80x94, (C3-C10)cycloalkyl-(CH2)mxe2x80x94, (C1-C6)alkyl or (C2-C9)heteroaryl-(CH2)mxe2x80x94, wherein m is an interger from zero to four; wherein each of said phenyl, naphthyl, (C3-C10)cycloalkyl or (C2-C9)heteroaryl moieties of said phenyl-(CH2)mxe2x80x94, naphthyl-(CH2)mxe2x80x94, (C3-C10)cycloalkyl-(CH2)mxe2x80x94 or (C2-C9)heteroaryl-(CH2)mxe2x80x94 groups may optionally be substituted with one or more substituents independently selected from hydrogen, deuterium, halo, CN, (C1-C6)alkyl optionally substituted with one or more fluorine atoms, hydroxy, hydroxy-(C1-C6)alkyl, (C1-C6)alkoxy optionally substituted with one or more fluorine atoms, (C1-C6)alkoxy(C1-C6)alkyl, HOxe2x80x94(Cxe2x95x90O)xe2x80x94, (C1-C6)alkyl-Oxe2x80x94(Cxe2x95x90O)xe2x80x94, HOxe2x80x94(Cxe2x95x90O)xe2x80x94(C1-C6)alkyl, (C1-C6)alkyl-Oxe2x80x94(Cxe2x95x90O)xe2x80x94(C1-C6)alkyl, (C1-C6)alkyl-(Cxe2x95x90O)xe2x80x94Oxe2x80x94, (C1-C6)alkyl-(Cxe2x95x90O)xe2x80x94Oxe2x80x94(C1-C6)alkyl, H(Oxe2x95x90C)xe2x80x94, H(Oxe2x95x90C)xe2x80x94(C1-C6)alkyl, (C1-C6)alkyl(Oxe2x95x90C)xe2x80x94, (C1-C6)alkyl(Oxe2x95x90C)xe2x80x94(C1-C6)alkyl, NO2, amino, (C1-C6)alkylamino, [(C1-C6)alkyl]2amino, amino(C1-C6)alkyl, (C1-C6)alkylamino(C1-C6)alkyl, [(C1-C6)alkyl]2amino(C1-C6)alkyl, H2Nxe2x80x94(Cxe2x95x90O)xe2x80x94, (C1-C6)alkyl-NHxe2x80x94(Cxe2x95x90O)xe2x80x94, [(C1-C6)alkyl]2Nxe2x80x94(Cxe2x95x90O)xe2x80x94, H2N(Cxe2x95x90O)xe2x80x94(C1-C6)alkyl, (C1-C6)alkyl-HN(Cxe2x95x90O)xe2x80x94(C1-C6)alkyl, [(C1-C6)alkyl]2Nxe2x80x94(Cxe2x95x90O)xe2x80x94(C1-C6)alkyl, H(Oxe2x95x90C)xe2x80x94NHxe2x80x94, (C1-C6)alkyl(Cxe2x95x90O)xe2x80x94NH, (C1-C6)alkyl(Cxe2x95x90O)xe2x80x94[NH](C1-C6)alkyl, (C1-C6)alkyl(Cxe2x95x90O)xe2x80x94[N(C1-C6)alkyl](C1-C6)alkyl, (C1-C6)alkyl-Sxe2x80x94, (C1-C6)alkyl-(Sxe2x95x90O)xe2x80x94, (C1-C6)alkyl-SO2xe2x80x94, (C1-C6)alkyl-SO2xe2x80x94NHxe2x80x94, H2Nxe2x80x94SO2xe2x80x94, H2Nxe2x80x94SO2xe2x80x94(C1-C6)alkyl, (C1-C6)alkylHNxe2x80x94SO2xe2x80x94(C1-C6)alkyl, [(C1-C6)alkyl]2Nxe2x80x94SO2xe2x80x94(C1-C6)alkyl, CF3SO3xe2x80x94, (C1-C6)alkyl-SO3xe2x80x94, phenyl, phenoxy, benzyloxy, (C3-C10)cycloalkyl, (C2-C9)heterocycloalkyl, and (C2-C9)heteroaryl;
R3 is hydrogen, deuterium, (C1-C10)alkyl, (C3-C10)cycloalkyl-(CH2)nxe2x80x94, (C2-C9)heterocycloalkyl-(CH2)nxe2x80x94, (C2-C9)heteroaryl-(CH2)nxe2x80x94 or aryl-(CH2)nxe2x80x94; wherein n is an interger from zero to six;
wherein said R3 (C1-C10)alkyl group may optionally be-substituted with one or more substituents, independently selected from hydrogen, deuterium, halo, CN, (C1-C6)alkyl optionally substituted with one or more fluorine atoms, hydroxy, hydroxy-(C1-C6)alkyl, (C1-C6)alkoxy optionally substituted with one or more fluorine atoms, (C1-C6)alkoxy(C1-C6)alkyl, HOxe2x80x94(Cxe2x95x90O)xe2x80x94, (C1-C6)alkyl-Oxe2x80x94(Cxe2x95x90O)xe2x80x94, HOxe2x80x94(Cxe2x95x90O)xe2x80x94(C1-C6)alkyl, (C1-C6)alkyl-Oxe2x80x94(Cxe2x95x90O)xe2x80x94(C1-C6)alkyl, (C1-C6)alkyl-(Cxe2x95x90O)xe2x80x94Oxe2x80x94, (C1-C6)alkyl-(Cxe2x95x90O)xe2x80x94Oxe2x80x94(C1-C6)alkyl, H(Oxe2x95x90C)xe2x80x94, H(Oxe2x95x90C)xe2x80x94(C1-C6)alkyl, (C1-C6)alkyl(Oxe2x95x90C)xe2x80x94, (C1-C6)alkyl(Oxe2x95x90C)xe2x80x94(C1-C6)alkyl, NO2, amino, (C1-C6)alkylamino, [(C1-C6)alkyl]2amino, amino(C1-C6)alkyl, (C1-C6)alkylamino(C1-C6)alkyl, [(C1-C6)alkyl]2amino(C1-C6)alkyl, H2Nxe2x80x94(Cxe2x95x90O)xe2x80x94, (C1-C6)alkyl-NHxe2x80x94(Cxe2x95x90O)xe2x80x94, [(C1-C6)alkyl]2Nxe2x80x94(Cxe2x95x90O)xe2x80x94, H2N(Cxe2x95x90O)xe2x80x94(C1-C6)alkyl, (C1-C6)alkyl-HN(Cxe2x95x90O)xe2x80x94(C1-C6)alkyl, [(C1-C6)alkyl]2Nxe2x80x94(Cxe2x95x90O)xe2x80x94(C1-C6)alkyl, H(Oxe2x95x90C)xe2x80x94NHxe2x80x94, (C1-C6)alkyl(Cxe2x95x90O)xe2x80x94NH, (C1-C6)alkyl(Cxe2x95x90O)xe2x80x94[NH](C1-C6)alkyl, (C1-C6)alkyl(Cxe2x95x90O)xe2x80x94[N(C1-C6)alkyl](C1-C6)alkyl, (C1-C6)alkyl-Sxe2x80x94, (C1-C6)alkyl-(Sxe2x95x90O)xe2x80x94, (C1-C6)alkyl-SO2xe2x80x94, (C1-C6)alkyl-SO2xe2x80x94NHxe2x80x94, H2Nxe2x80x94SO2xe2x80x94, H2Nxe2x80x94SO2xe2x80x94(C1-C6)alkyl, (C1-C6)alkylHNxe2x80x94SO2xe2x80x94(C1-C6)alkyl, [(C1-C6)alkyl]2Nxe2x80x94SO2xe2x80x94(C1-C6)alkyl, CF3SO3xe2x80x94, (C1-C6)alkyl-SO3xe2x80x94, (C3-C10)cycloalkyl, (C2-C9)heterocycloalkyl, and (C2-C9)heteroaryl; and wherein any of the carbon-carbon single bonds of said (C1-C10)alkyl may optionally be replaced by a carbon-carbon double bond;
wherein the (C3-C10)cycloalkyl moiety of said R3 (C3-C10)cycloalkyl-(CH2)nxe2x80x94 group may optionally be substituted by one to three substitutents independently selected from the group consisting of hydrogen, deuterium, halo, CN, (C1-C6)alkyl optionally substituted with one or more fluorine atoms, hydroxy, hydroxy-(C1-C6)alkyl, (C1-C6)alkoxy optionally substituted with one or more fluorine atoms, (C1-C6)alkoxy(C1-C6)alkyl, HOxe2x80x94(Cxe2x95x90O)xe2x80x94, (C1-C6)alkyl-Oxe2x80x94(Cxe2x95x90O)xe2x80x94, HOxe2x80x94(Cxe2x95x90O)xe2x80x94(C1-C6)alkyl, (C1-C6)alkyl-Oxe2x80x94(Cxe2x95x90O)xe2x80x94(C1-C6)alkyl, (C1-C6)alkyl-(Cxe2x95x90O)xe2x80x94Oxe2x80x94, (C1-C6)alkyl-(Cxe2x95x90O)xe2x80x94Oxe2x80x94(C1-C6)alkyl, H(Oxe2x95x90C)xe2x80x94, H(Oxe2x95x90C)xe2x80x94(C1-C6)alkyl, (C1-C6)alkyl(Oxe2x95x90C)xe2x80x94, (C1-C6)alkyl(Oxe2x95x90C)xe2x80x94(C1-C6)alkyl, NO2, amino, (C1-C6)alkylamino, [(C1-C6)alkyl]2amino, amino(C1-C6)alkyl, (C1-C6)alkylamino(C1-C6)alkyl, [(C1-C6)alkyl]2amino(C1-C6)alkyl, H2Nxe2x80x94(Cxe2x95x90O)xe2x80x94, (C1-C6)alkyl-NHxe2x80x94(Cxe2x95x90O)xe2x80x94, [(C1-C6)alkyl]2Nxe2x80x94(Cxe2x95x90O)xe2x80x94, H2N(Cxe2x95x90O)xe2x80x94(C1-C6)alkyl, (C1-C6)alkyl-HN(Cxe2x95x90O)xe2x80x94(C1-C6)alkyl, [(C1-C6)alkyl]2Nxe2x80x94(Cxe2x95x90O)xe2x80x94(C1-C6)alkyl, H(Oxe2x95x90C)xe2x80x94NHxe2x80x94, (C1-C6)alkyl(Cxe2x95x90O)xe2x80x94NH, (C1-C6)alkyl(Cxe2x95x90O)xe2x80x94[NH](C1-C6)alkyl, (C1-C6)alkyl(Cxe2x95x90O)xe2x80x94[N(C1-C6)alkyl](C1-C6)alkyl, (C1-C6)alkyl-Sxe2x80x94, (C1-C6)alkyl-(Sxe2x95x90O)xe2x80x94, (C1-C6)alkyl-SO2xe2x80x94, (C1-C6)alkyl-SO2xe2x80x94NHxe2x80x94, H2Nxe2x80x94SO2xe2x80x94, H2Nxe2x80x94SO2xe2x80x94(C1-C6)alkyl, (C1-C6)alkylHNxe2x80x94SO2xe2x80x94(C1-C6)alkyl, [(C1-C6)alkyl]2Nxe2x80x94SO2xe2x80x94(C1-C6)alkyl, CF3SO3xe2x80x94, (C1-C6)alkyl-SO3xe2x80x94, (C3-C10)cycloalkyl, (C2-C9)heterocycloalkyl, and (C2-C9)heteroaryl;
wherein the (C2-C9)heterocycloalkyl moiety of said R3 (C2-C9)heterocycloalkyl-(CH2)nxe2x80x94 group has from one to three heteroatoms independently selected from nitrogen, sulfur, oxygen,  greater than S(xe2x95x90O),  greater than SO2 or  greater than NR6, wherein said (C2-C9)heterocycloalkyl moiety of said (C2-C9)heterocycloalkyl-(CH2)nxe2x80x94 group may optionally be substituted on any of the ring carbon atoms capable of forming an additional bond with a substituent independently selected from the group consisting of hydrogen, deuterium, halo, CN, (C1-C6)alkyl optionally substituted with one or more fluorine atoms, hydroxy, hydroxy-(C1-C6)alkyl, (C1-C6)alkoxy optionally substituted with one or more fluorine atoms, (C1-C6)alkoxy(C1-C6)alkyl, HOxe2x80x94(Cxe2x95x90O)xe2x80x94, (C1-C6)alkyl-Oxe2x80x94(Cxe2x95x90O), HOxe2x80x94(Cxe2x95x90O)xe2x80x94(C1-C6)alkyl, (C1-C6)alkyl-Oxe2x80x94(Cxe2x95x90O)xe2x80x94(C1-C6)alkyl, (C1-C6)alkyl-(Cxe2x95x90O)xe2x80x94Oxe2x80x94, (C1-C6)alkyl-(Cxe2x95x90O)xe2x80x94Oxe2x80x94(C1-C6)alkyl, H(Oxe2x95x90C)xe2x80x94, H(Oxe2x95x90C)xe2x80x94(C1-C6)alkyl, (C1-C6)alkyl(Oxe2x95x90C)xe2x80x94, (C1-C6)alkyl(Oxe2x95x90C)xe2x80x94(C1-C6)alkyl, NO2, amino, (C1-C6)alkylamino, [(C1-C6)alkyl]2amino, amino(C1-C6)alkyl, (C1-C6)alkylamino(C1-C6)alkyl, [(C1-C6)alkyl]2amino(C1-C6)alkyl, H2Nxe2x80x94(Cxe2x95x90O)xe2x80x94, (C1-C6)alkyl-NHxe2x80x94(Cxe2x95x90O)xe2x80x94, [(C1-C6)alkyl]2Nxe2x80x94(Cxe2x95x90O)xe2x80x94, H2N(Cxe2x95x90O)xe2x80x94(C1-C6)alkyl, (C1-C6)alkyl-HN(Cxe2x95x90O)xe2x80x94(C1-C6)alkyl, [(C1-C6)alkyl]2Nxe2x80x94(Cxe2x95x90O)xe2x80x94(C1-C6)alkyl, H(Oxe2x95x90C)xe2x80x94NHxe2x80x94, (C1-C6)alkyl(Cxe2x95x90O)xe2x80x94NH, (C1-C6)alkyl(Cxe2x95x90O)xe2x80x94[NH](C1-C6)alkyl, (C1-C6)alkyl(Cxe2x95x90O)xe2x80x94[N(C1-C6)alkyl](C1-C6)alkyl, (C1-C6)alkyl-Sxe2x80x94, (C1-C6)alkyl-(Sxe2x95x90O)xe2x80x94, (C1-C6)alkyl-SO2xe2x80x94, (C1-C6)alkyl-SO2xe2x80x94NHxe2x80x94, H2Nxe2x80x94SO2xe2x80x94, H2Nxe2x80x94SO2xe2x80x94(C1-C6)alkyl, (C1-C6)alkylHNxe2x80x94SO2xe2x80x94(C1-C6)alkyl, [(C1-C6)alkyl]2Nxe2x80x94SO2xe2x80x94(C1-C6)alkyl, CF3SO3xe2x80x94, (C1-C6)alkyl-SO3xe2x80x94, phenyl, (C3-C10)cycloalkyl, (C2-C9)heterocycloalkyl, and (C2-C9)heteroaryl;
wherein the (C2-C9)heteroaryl moiety of said R3 (C2-C9)heteroaryl-(CH2)nxe2x80x94 group has from one to three heteroatoms independently selected from nitrogen, sulfur or oxygen wherein said (C2-C9)heteroaryl moiety of said (C2-C9)heteroaryl-(CH2)nxe2x80x94 group may optionally be substituted on any of the ring carbon atoms capable of forming an additional bond with a substituent selected from the group consisting of hydrogen, deuterium, halo, CN, (C1-C6)alkyl optionally substituted with one or more fluorine atoms, hydroxy, hydroxy-(C1-C6)alkyl, (C1-C6)alkoxy optionally substituted with one or more fluorine atoms, (C1-C6)alkoxy(C1-C6)alkyl, HOxe2x80x94(Cxe2x95x90O)xe2x80x94, (C1-C6)alkyl-Oxe2x80x94(Cxe2x95x90O)xe2x80x94, HOxe2x80x94(Cxe2x95x90O)xe2x80x94(C1-C6)alkyl, (C1-C6)alkyl-Oxe2x80x94(Cxe2x95x90O)xe2x80x94(C1-C6)alkyl, (C1-C6)alkyl-(Cxe2x95x90O)xe2x80x94Oxe2x80x94, (C1-C6)alkyl-(Cxe2x95x90O)xe2x80x94Oxe2x80x94(C1-C6)alkyl, H(Oxe2x95x90C)xe2x80x94, H(Oxe2x95x90C)xe2x80x94(C1-C6)alkyl, (C1-C6)alkyl(Oxe2x95x90C)xe2x80x94, (C1-C6)alkyl(Oxe2x95x90C)xe2x80x94(C1-C6)alkyl, NO2, amino, (C1-C6)alkylamino, [(C1-C6)alkyl]2amino, amino(C1-C6)alkyl, (C1-C6)alkylamino(C1-C6)alkyl, [(C1-C6)alkyl]2amino(C1-C6)alkyl, H2Nxe2x80x94(Cxe2x95x90O)xe2x80x94, (C1-C6)alkyl-NHxe2x80x94(Cxe2x95x90O)xe2x80x94, [(C1-C6)alkyl]2Nxe2x80x94(Cxe2x95x90O)xe2x80x94, H2N(Cxe2x95x90O)xe2x80x94(C1-C6)alkyl, (C1-C6)alkyl-HN(Cxe2x95x90O)xe2x80x94(C1-C6)alkyl, [(C1-C6)alkyl]2Nxe2x80x94(Cxe2x95x90O)xe2x80x94(C1-C6)alkyl, H(Oxe2x95x90C)xe2x80x94NHxe2x80x94, (C1-C6)alkyl(Cxe2x95x90O)xe2x80x94NH, (C1-C6)alkyl(Cxe2x95x90O)xe2x80x94[NH](C1-C6)alkyl, (C1-C6)alkyl(Cxe2x95x90O)xe2x80x94[N(C1-C6)alkyl](C1-C6)alkyl, (C1-C6)alkyl-Sxe2x80x94, (C1-C6)alkyl-(Sxe2x95x90O)xe2x80x94, (C1-C6)alkyl-SO2xe2x80x94, (C1-C6)alkyl-SO2xe2x80x94NHxe2x80x94, H2Nxe2x80x94SO2xe2x80x94, H2Nxe2x80x94SO2xe2x80x94(C1-C6)alkyl, (C1-C6)alkylHNxe2x80x94SO2xe2x80x94(C1-C6)alkyl, [(C1-C6)alkyl]2Nxe2x80x94SO2xe2x80x94(C1-C6)alkyl, CF3SO3xe2x80x94, (C1-C6)alkyl-SO3xe2x80x94, phenyl, (C3-C10)cycloalkyl, (C2-C9)heterocycloalkyl, and (C2-C9)heteroaryl; and
wherein said aryl moiety of said R3 aryl-(CH2)nxe2x80x94 group is optionally substituted phenyl or naphthyl, wherein said phenyl and naphthyl may optionally be substituted with from one to three substituents independently selected from the group consisting of hydrogen, deuterium, halo, CN, (C1-C6)alkyl optionally substituted with one or more fluorine atoms, hydroxy, hydroxy-(C1-C6)alkyl, (C1-C6)alkoxy optionally substituted with one or more fluorine atoms, (C1-C6)alkoxy(C1-C6)alkyl, HOxe2x80x94(Cxe2x95x90O)xe2x80x94, (C1-C6)alkyl-Oxe2x80x94(Cxe2x95x90O)xe2x80x94, HOxe2x80x94(Cxe2x95x90O)xe2x80x94(C1-C6)alkyl, (C1-C6)alkyl-Oxe2x80x94(Cxe2x95x90O)xe2x80x94(C1-C6)alkyl, (C1-C6)alkyl-(Cxe2x95x90O)xe2x80x94Oxe2x80x94, (C1-C6)alkyl-(Cxe2x95x90O)xe2x80x94Oxe2x80x94(C1-C6)alkyl, H(Oxe2x95x90C)xe2x80x94, H(Oxe2x95x90C)xe2x80x94(C1-C6)alkyl, (C1-C6)alkyl(Oxe2x95x90C)xe2x80x94, (C1-C6)alkyl(Oxe2x95x90C)xe2x80x94(C1-C6)alkyl, NO2, amino, (C1-C6)alkylamino, [(C1-C6)alkyl]2amino, amino(C1-C6)alkyl, (C1-C6)alkylamino(C1-C6)alkyl, [(C1-C6)alkyl]2amino(C1-C6)alkyl, H2Nxe2x80x94(Cxe2x95x90O)xe2x80x94, (C1-C6)alkyl-NHxe2x80x94(Cxe2x95x90O)xe2x80x94, [(C1-C6)alkyl]2Nxe2x80x94(Cxe2x95x90O)xe2x80x94, H2N(Cxe2x95x90O)xe2x80x94(C1-C6)alkyl, (C1-C6)alkyl-HN(Cxe2x95x90O)xe2x80x94(C1-C6)alkyl, [(C1-C6)alkyl]2Nxe2x80x94(Cxe2x95x90O)xe2x80x94(C1-C6)alkyl, H(Oxe2x95x90C)xe2x80x94NHxe2x80x94, (C1-C6)alkyl(Cxe2x95x90O)xe2x80x94NH, (C1-C6)alkyl(Cxe2x95x90O)xe2x80x94[NH](C1-C6)alkyl, (C1-C6)alkyl(Cxe2x95x90O)xe2x80x94[N(C1-C6)alkyl](C1-C6)alkyl, (C1-C6)alkyl-Sxe2x80x94, (C1-C6)alkyl-(Sxe2x95x90O)xe2x80x94, (C1-C6)alkyl-SO2xe2x80x94, (C1-C6)alkyl-SO2xe2x80x94NHxe2x80x94, H2Nxe2x80x94SO2xe2x80x94, H2Nxe2x80x94SO2xe2x80x94(C1-C6)alkyl, (C1-C6)alkylHNxe2x80x94SO2xe2x80x94(C1-C6)alkyl, [(C1-C6)alkyl]2Nxe2x80x94SO2xe2x80x94(C1-C6)alkyl, CF3SO3xe2x80x94, (C1-C6)alkyl-SO3xe2x80x94, phenyl, (C3-C10)cycloalkyl, (C2-C9)heterocycloalkyl, and (C2-C9)heteroaryl.
The present invention also relates to the pharmaceutically acceptable acid addition salts of compounds of the formula XXXI. The acids which are used to prepare the pharmaceutically acceptable acid addition salts of the aforementioned base compounds of this invention are those which form non-toxic acid addition salts, i.e., salts containing pharmacologically acceptable anions, such as the hydrochloride, hydrobromide, hydroiodide, nitrate, sulfate, bisulfate, phosphate, acid phosphate, acetate, lactate, citrate, acid citrate, tartrate, bitartrate, succinate, maleate, fumarate, gluconate, saccharate, benzoate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate and pamoate [i.e., 1,1xe2x80x2-methylene-bis-(2-hydroxy-3-naphthoate)]salts.
The invention also relates to base addition salts of formula XXXI. The chemical bases that may be used as reagents to prepare pharmaceutically acceptable base salts of those compounds of formula I that are acidic in nature are those that form non-toxic base salts with such compounds. Such non-toxic base salts include, but are not limited to those derived from such pharmacologically acceptable cations such as alkali metal cations (eq., potassium and sodium) and alkaline earth metal cations (e.g., calcium and magnesium), ammonium or water-soluble amine addition salts such as N-methylglucamine-(meglumine), and the lower alkanolammonium and other base salts of pharmaceutically acceptable organic amines.
The compounds of this invention may contain olefin-like double bonds. When such bonds are present, the compounds of the invention exist as cis and trans configurations and as mixtures thereof.
Unless otherwise indicated, the alkyl and alkenyl groups referred to herein, as well as the alkyl moieties of other groups referred to herein (e.g., alkoxy), may be linear or branched, and they may also be cyclic (e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl) or be linear or branched and contain cyclic moieties. Unless otherwise indicated, halogen includes fluorine, chlorine, bromine, and iodine.
(C3-C10)Cycloalkyl when used herein refers to cycloalkyl groups containing zero to two levels of unsaturation such as cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, 1,3-cyclohexadiene, cycloheptyl, cycloheptenyl, bicyclo[3.2.1]octane, norbornanyl etc.
(C2-C9)Heterocycloalkyl when used herein refers to pyrrolidinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydropyranyl, pyranyl, thiopyranyl, aziridinyl, oxiranyl, methylenedioxyl, chromenyl, isoxazolidinyl, 1,3-oxazolidin-3-yl, isothiazolidinyl, 1,3-thiazolidin-3-yl, 1,2-pyrazolidin-2-yl, 1,3-pyrazolidin-1-yl, piperidinyl, thiomorpholinyl, 1,2-tetrahydrothiazin-2-yl, 1,3-tetrahydrothiazin-3-yl, tetrahydrothiadiazinyl, morpholinyl, 1,2-tetrahydrodiazin-2-yl, 1,3-tetrahydrodiazin-1-yl, tetrahydroazepinyl, piperazinyl, chromanyl, etc. One of ordinary skill in the art will understand that the connection of said (C2-C9)heterocycloalkyl rings is through a carbon or a Sp3 hybridized nitrogen heteroatom.
(C2-C9)Heteroaryl when used herein refers to furyl, thienyl, thiazolyl, pyrazolyl, isothiazolyl, oxazolyl, isoxazolyl, pyrrolyl, triazolyl, tetrazolyl, imidazolyl, 1,3,5-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,3-oxadiazolyl, 1,3,5-thiadiazolyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, 1,2,4-triazinyl, 1,2,3-triazinyl, 1,3,5-triazinyl, pyrazolo[3,4-b]pyridinyl, cinnolinyl, pteridinyl, purinyl, 6,7-dihydro-5H-[1]pyrindinyl, benzo[b]thiophenyl, 5,6,7,8-tetrahydro-quinolin-3-yl, benzoxazolyl, benzothiazolyl, benzisothiazolyl, benzisoxazolyl, benzimidazolyl, thianaphthenyl, isothianaphthenyl, benzofuranyl, isobenzofuranyl, isoindolyl, indolyl, indolizinyl, indazolyl, isoquinolyl, quinolyl, phthalazinyl, quinoxalinyl, quinazolinyl, benzoxazinyl; etc. One of ordinary skill in the art will understand that the connection of said (C2-C9)heterocycloalkyl rings is through a carbon atom or a Sp3 hybridized nitrogen heteroatom.
Aryl when used herein refers to phenyl or naphthyl.
The compounds of this invention include all conformational isomers (e.g., cis and trans isomers) and all optical isomers of compounds of the formula I (e.g., enantiomers and diastereomers), as well as racemic, diastereomeric and other mixtures of such isomers.
The following reaction Schemes illustrate the preparation of the compounds of the present invention. Unless otherwise indicated R1, R2, and R3 in the reaction Schemes and the discussion that follow are defined as above. The definition of remaining variables is as follows:
R4 is (C2-C9)heteroaryl, (C2-C9)heterocycloalkyl, R5R6N-sulfonyl or a group of the formula 
wherein R5 is hydrogen, deuterium, (C1-C6)alkyl, hydroxy, (C1-C6)alkoxy, hydroxy(C1-C6)alkyl, (C1-C6)alkoxy(Cxe2x95x90O)xe2x80x94, (C3-C10)cycloalkyl-(CH2)pxe2x80x94, (C2-C9)heterocycloalkyl-(CH2)pxe2x80x94, (C2-C9)heteroaryl-(CH2)pxe2x80x94, phenyl-(CH2)pxe2x80x94, or naphthyl-(CH2)pxe2x80x94, wherein p is an integer from zero to four; wherein said (C2-C9)heterocycloalkyl, (C2-C9)heteroaryl, phenyl and naphthyl groups of said (C2-C9)heterocycloalkyl-(CH2)pxe2x80x94, (C2-C9)heteroaryl-(CH2)pxe2x80x94, phenyl-(CH2)pxe2x80x94, or naphthyl-(CH2)pxe2x80x94 may be optionally substituted on any of the ring atoms capable of supporting an additional bond with a substituent selected from the group consisting of hydrogen, halo, CN, (C1-C6)alkyl optionally substituted with one or more fluorine atoms, hydroxy, hydroxy-(C1-C6)alkyl, (C1-C6)alkoxy optionally substituted with one or more fluorine atoms, (C1-C6)alkoxy(C1-C6)alkyl, HOxe2x80x94(Cxe2x95x90O)xe2x80x94, (C1-C6)alkyl-Oxe2x80x94(Cxe2x95x90O)xe2x80x94, HOxe2x80x94(Cxe2x95x90O)xe2x80x94(C1-C6)alkyl, (C1-C6)alkyl-Oxe2x80x94(Cxe2x95x90O)xe2x80x94(C1-C6)alkyl, (C1-C6)alkyl-(Cxe2x95x90O)xe2x80x94Oxe2x80x94, (C1-C6)alkyl-(Cxe2x95x90O)xe2x80x94Oxe2x80x94(C1-C6)alkyl, H(Oxe2x95x90C)xe2x80x94, H(Oxe2x95x90C)xe2x80x94(C1-C6)alkyl, (C1-C6)alkyl(Oxe2x95x90C)xe2x80x94, (C1-C6)alkyl(Oxe2x95x90C)xe2x80x94(C1-C6)alkyl, NO2, amino, (C1-C6)alkylamino, [(C1-C6)alkyl]2amino, amino(C1-C6)alkyl, (C1-C6)alkylamino (C1-C6)alkyl, [(C1-C6)alkyl]2amino(C1-C6)alkyl, H2Nxe2x80x94(Cxe2x95x90O)xe2x80x94, (C1-C6)alkyl-NHxe2x80x94(Cxe2x95x90O)xe2x80x94, [(C1-C6)alkyl]2Nxe2x80x94(Cxe2x95x90O)xe2x80x94, H2N(Cxe2x95x90O)xe2x80x94(C1-C6)alkyl, (C1-C6)alkyl-HN(Cxe2x95x90O)xe2x80x94(C1-C6)alkyl, [(C1-C6)alkyl]2Nxe2x80x94(Cxe2x95x90O)xe2x80x94(C1-C6)alkyl, H(Oxe2x95x90C)xe2x80x94NHxe2x80x94, (C1-C6)alkyl(Cxe2x95x90O)xe2x80x94NH, (C1-C6)alkyl(Cxe2x95x90O)xe2x80x94[NH](C1-C6)alkyl, (C1-C6)alkyl(Cxe2x95x90O)xe2x80x94[N(C1-C6)alkyl](C1-C6)alkyl, (C1-C6)alkyl-Sxe2x80x94, (C1-C6)alkyl-(Sxe2x95x90O)xe2x80x94, (C1-C6)alkyl-SO2xe2x80x94, (C1-C6)alkyl-SO2xe2x80x94NHxe2x80x94, H2Nxe2x80x94SO2xe2x80x94, H2Nxe2x80x94SO2xe2x80x94(C1-C6)alkyl, (C1-C6)alkylHNxe2x80x94SO2xe2x80x94(C1-C6)alkyl, [(C1-C6)alkyl]2Nxe2x80x94SO2xe2x80x94(C1-C6)alkyl, CF3SO3xe2x80x94, (C1-C6)alkyl-SO3xe2x80x94, phenyl, (C3-C10)cycloalkyl, (C2-C9)heterocycloalkyl, and (C2-C9)heteroaryl;
or R5 and R6 together with the nitrogen atom to which they are attached form a (C2-C9)heterocycloalkyl group wherein any of the ring atoms of said (C2-C9)heterocycloalkyl group may optionally be substituted with a substituent selected from the group consisting of hydrogen, halo, CN, (C1-C6)alkyl optionally substituted with one or more fluorine atoms, hydroxy, hydroxy-(C1-C6)alkyl, (C1-C6)alkoxy optionally substituted with one or more fluorine atoms, (C1-C6)alkoxy(C1-C6)alkyl, HOxe2x80x94(Cxe2x95x90O)xe2x80x94, (C1-C6)alkyl-Oxe2x80x94(Cxe2x95x90O)xe2x80x94, HOxe2x80x94(Cxe2x95x90O)xe2x80x94(C1-C6)alkyl, (C1-C6)alkyl-Oxe2x80x94(Cxe2x95x90O)xe2x80x94(C1-C6)alkyl, (C1-C6)alkyl-(Cxe2x95x90O)xe2x80x94Oxe2x80x94, (C1-C6)alkyl-(Cxe2x95x90O)xe2x80x94Oxe2x80x94(C1-C6)alkyl, H(Oxe2x95x90C)xe2x80x94, H(Oxe2x95x90C)xe2x80x94(C1-C6)alkyl, (C1-C6) alkyl(Oxe2x95x90C)xe2x80x94, (C1-C6)alkyl(Oxe2x95x90C)xe2x80x94(C1-C6)alkyl, NO2, amino, (C1-C6)alkylamino, [(C1-C6)alkyl]2amino, amino(C1-C6)alkyl, (C1-C6)alkylamino (C1-C6)alkyl, [(C1-C6)alkyl]2amino(C1-C6)alkyl, H2Nxe2x80x94(Cxe2x95x90O)xe2x80x94, (C1-C6)alkyl-NHxe2x80x94(Cxe2x95x90O)xe2x80x94, [(C1-C6)alkyl]2Nxe2x80x94(Cxe2x95x90O)xe2x80x94, H2N(Cxe2x95x90O)xe2x80x94(C1-C6)alkyl, (C1-C6)alkyl-HN(Cxe2x95x90O)xe2x80x94(C1-C6)alkyl, [(C1-C6)alkyl]2Nxe2x80x94(Cxe2x95x90O)xe2x80x94(C1-C6)alkyl, H(Oxe2x95x90C)xe2x80x94NHxe2x80x94, (C1-C6)alkyl(Cxe2x95x90O)xe2x80x94NH, (C1-C6)alkyl(Cxe2x95x90O)xe2x80x94[NH](C1-C6)alkyl, (C1-C6)alkyl(Cxe2x95x90O)xe2x80x94[N(C1-C6)alkyl](C1-C6)alkyl, (C1-C6)alkyl-Sxe2x80x94, (C1-C6)alkyl-(Sxe2x95x90O)xe2x80x94, (C1-C6)alkyl-SO2xe2x80x94, (C1-C6)alkyl-SO2xe2x80x94NHxe2x80x94, H2Nxe2x80x94SO2xe2x80x94, H2Nxe2x80x94SO2xe2x80x94(C1-C6)alkyl, (C1-C6)alkylHNxe2x80x94SO2xe2x80x94(C1-C6)alkyl, [(C1-C6)alkyl]2Nxe2x80x94SO2xe2x80x94(C1-C6)alkyl, CF3SO3xe2x80x94, (C1-C6)alkyl-SO3xe2x80x94, phenyl, (C3-C10)cycloalkyl, (C2-C9)heterocycloalkyl, and (C2-C9)heteroaryl;
R6 is hydrogen, deuterium, (C1-C6)alkyl or amino;
X is NR7 or S wherein R7 is defined as R4 above or is H, COCH3, SO2CH3 or CN; and
with the proviso that when R4 is a five-membered heterocyclic group, either R2 or R3 must be substituted by a functional group other than (C1-C6)alkyl, hydroxy(C1-C6)alkyl, (C1-C6)alkoxy, (C1-C6)alkyl-(Cxe2x95x90O)xe2x80x94Oxe2x80x94, (C1-C6)alkyl-(Cxe2x95x90O)xe2x80x94Oxe2x80x94(C1-C6)alkyl, amino, (C1-C6)alkylamino, [(C1-C6)alkyl]2amino, amino(C1-C6)alkyl, benzofuryl, indolyl, azacycloalkyl, azabicycloalkyl or benzopiperidinyl. 
Compounds of formula I may be prepared by methods described in WO 98/38167, which is incorporated by reference in its entirety.
In reaction 1 of Scheme 1, the alcohol compound of formula XII is converted to the corresponding acetate compound of formula XI by reacting XII with acetic anhydride in the presence of 4-dimethylaminopyridine (DMAP) and pyridine. The reaction 1 stirred at a temperature between about 0xc2x0 C. to about room temperature, preferably about 0xc2x0 C., for a time period between about 1 hour to about 3 hours, preferably about 2 hours.
In reaction 2 of Scheme 1, the compound of formula XI is converted to the corresponding compound of formula X by reacting Xi with N,N-dimethylformamide dimethyl acetal in the presence of a polar protic solvent, such as methanol. The reaction is stirred at a temperature between about 40xc2x0 C. to about 60xc2x0 C., preferably about 50xc2x0 C., for a time period between about 30 minutes to about 2 hours, preferably about 1 hour.
In reaction 3 of Scheme 1, the compound of formula X is converted to the corresponding triazole compound of formula IX by reacting X with hydrazine in the presence of acetic acid. The reaction is stirred at a temperature between about 40xc2x0 C. to about 60xc2x0 C., preferably about 50xc2x0 C., for a time period between about 30 minutes to about 2 hours, preferably about 1 hour.
In reaction 4 of Scheme 1, the compound of formula IX is converted to the corresponding compound of formula II by deprotecting IX with potassium carbonate in the presence of methanol at room temperature overnight.
In reaction 1 of Scheme 2, the lactone compound of formula XIV is converted to the corresponding hydrazide compound of formula XIII by reacting XIV with hydrazine in a polar protic solvent, such as methanol. The reaction is stirred at room temperature overnight.
In reaction 2 of Scheme 2, the hydrazine compound of formula XIII is converted to the corresponding 1,2,4-oxadiazole compound of formula III by reacting XIII with cyanogen bromide in the presence of dioxane and water. The reaction is heated to reflux for a time period between about 30 minutes to about 2 hours, preferably about 1 hour.
In reaction 3 of Scheme 2, the hydrazide compound of formula XIII is converted to the corresponding compound of formula IV by reacting XIII with CDI in the presence of a base, such as triethylamine, and a polar aprotic solvent, such as tetrahydrofuran. The reaction is stirred at room temperature for a time period between about 10 hours to about 20 hours, preferably overnight.
In reaction 1 of Scheme 3, the lactone compound of formula XVIII is converted to the corresponding compound of formula XVII by reacting XVIII with aminoacetaldehyde dimethyl acetal in the presence of dioxane. The reaction is stirred overnight at a temperature between about 30xc2x0 C. to about 70xc2x0 C., preferably about 50xc2x0 C.
In reaction 2 of Scheme 3, the alcohol compound of formula XVII is converted to the corresponding acetate compound of formula XVI according to the procedure described above in reaction 1 of Scheme 1.
In reaction 3 of Scheme 3, the compound of formula XVI is converted to the corresponding imidazole compound of formula XV by reacting XVI with ammonium acetate in the presence of acetic acid. The reaction is stirred at a temperature between about 105xc2x0 C. to about 125xc2x0 C., preferably about 115xc2x0 C., for a time period between about 3 hours to about 5 hours, preferably about 4 hours.
In reaction 4 of Scheme 3, the compound of formula XV is converted to the corresponding compound of formula V according to the procedure described above in reaction 4 of Scheme 1.
In reaction 1 of Scheme 4, the epoxide compound of formula XXI is converted to the corresponding compound of formula XX by reacting XXI with a compound of the formula, CHR3R4, in the presence of a base, such as n-butyllithium, and a polar aprotic solvent, such as tetrahydrofuran. The reaction is carried out at a temperature between about xe2x88x9278xc2x0 C. to about 0xc2x0 C., preferably about xe2x88x9278xc2x0 C., for a time period between about 1 hours to about 4 hours, preferably about 2 hours.
In reaction 2 of Scheme 4, the compound of formula XX is converted to the corresponding compound of formula XIX by removal of the carbobenzyloxy protecting group through hydrogenation of XX in the presence of palladium on carbon and a polar protic solvent, such as ethanol. The reaction is carried out at a temperature between about 0xc2x0 C. to room temperature, preferably room temperature, for a time period between about 1 hour to about 24 hours, preferably about 15 hours.
In reaction 3 of Scheme 4, the compound of formula XIX is converted to the corresponding compound of formula I by reacting XIX with a compound of the formula, R1xe2x80x94COxe2x80x94Cl, in the presence of a base, such as triethylamine, and a polar aprotic solvent, such as methylene chloride. The reaction is carried out at a temperature between about xe2x88x9220xc2x0 C. to about 40xc2x0 C., preferably about 0xc2x0 C., for a time period between about 1 hour to about 24 hours, preferably about 2 hours.
In reaction 1 of Scheme 5, the compound of formula XXVI is converted to the corresponding compound of formula XXV according to the procedure described above in reaction 1 of Scheme 1.
In reaction 2 of Scheme 5, the amide compound of formula XXV is converted to the thioacetamide compound of formula XXIV by reacting XXV with Lawesson""s Reagent, [2,4-bis(4-methoxyphenyl)-1,3-dithia-2,4-diphosphetane-2,4-disulfide], in the presence of a polar aprotic solvent, such as tetrahydrofuran. The reaction is carried out at a temperature between about 0xc2x0 C. to about 60xc2x0 C., preferably about 25xc2x0 C., for a time period between about 1 hour to about 24 hours, preferably about 5 hours.
In reaction 3 of Scheme 5, the thioacetamide compound of formula XXIV is converted to the corresponding compound of formula XXIII by first treating XXIV with methyl iodide, followed by reacting the compound so formed with ammonia in methyl alcohol. The reaction is carried out at a temperature between about 0xc2x0 C. to about 60xc2x0 C., preferably about 25xc2x0 C., for a time period between about 1 hour to about 24 hours, preferably about 15 hours.
In reaction 4 of Scheme 5, the compound of formula XXIII is converted to the corresponding compound of formula XXII by reacting XXII with (a) R8 sulfonyl chloride when R7 is R8S(O)2; (b) cyanogen bromide when R7 is cyano; (c) Lxe2x80x94Nxe2x95x90Cxe2x95x90O when R7 is an amide and L is a leaving group; or (d) an acyl chloride compound of the formula, R8xe2x80x94COxe2x80x94Cl, when R7 is R8C(O).
In reaction 5 of Scheme 5, the compound of formula XXII is converted to the corresponding compound of formula VI according to the procedure described above in reaction 1 of Scheme 1.
In reaction 1 of Scheme 6, the lactone of formula XXXII is converted to the corresponding compound of formula XXXI by reacting XXXII with a base, such as lithium hydroxide, in the presence of a mixture of water and a polar aprotic solvent, such as tetrahydrofuran. The reaction is carried out at a temperature between about 0xc2x0 C. to about 60xc2x0 C., preferably about 25xc2x0 C., for a time period between about 1 hour to about 24 hours, preferably about 2 hours.
In reaction 2 of Scheme 6, the compound of formula XXXI is converted to the corresponding compound of formula XXX by reacting XXXI with tert-butyidimethylsilyl chloride in the presence of imidazole and polar protic solvent, such as dimethylformamide. The reaction is carried out at a temperature between about 0xc2x0 C. to about 60xc2x0 C., preferably about 25xc2x0 C., for a time period between about 1 day to 7 days, preferably 1 day.
In reaction 3 of Scheme 6, the compound of formula XXX is converted to the corresponding compound of formula XXIX by reacting XXX with a compound of the formula 
in the presence of 1-hydroxybenzotriazole hydrate, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide and a polar aprotic solvent, such as methylene chloride. The reaction is carried out at a temperature between about 0xc2x0 C. to about 30xc2x0 C., preferably about 25xc2x0 C., for a time period between about 1 hour to about 24 hours, preferably about 25 hours.
In reaction 4 of Scheme 6, the compound of formula XXIX is converted to the corresponding oxazole compound of the formula XXVII by first oxidizing XXIX with the Dess-Martin periodinane oxidation reagent of the formula 
followed by treating the compound so formed with triphenylphosphine, triethylamine, hexachloroethane and a polar aprotic solvent, such as methylene chloride. The reaction is carried out at a temperature between about 0xc2x0 C. to about 40xc2x0 C., preferably about 25xc2x0 C., for a time period between about 5 hours to about 24 hours, preferably about 15 hours.
In reaction 5 of Scheme 6, the compound of formula XXIX is converted to the corresponding oxazoline compound of formula XXVIII by treating XXIX with triphenylphosphine, hexachloroethane, triethylamine and a polar aprotic solvent, such as methylene chloride. The reaction is carried out at a temperature between about 0xc2x0 C. to about 40xc2x0 C., preferably about 25xc2x0 C., for a time period between about 5 hours to about 24 hours, preferably about 15 hours.
In reaction 6 of Scheme 6, the compound of formula XXVII is converted to the corresponding compound of formula VII by treating XXVII with tert-butyl ammonium fluoride. The reaction is carried out at a temperature between about 0xc2x0 C. to about 40xc2x0 C., preferably about 25xc2x0 C., for a time period between about 1 hour to about 24 hours, preferably about 2 hours.
In reaction 7 of Scheme 6, the compound of formula XXVIII is converted to the corresponding compound of formula VII according to the procedure described above in reaction 6 of Scheme 6.
Unless indicated otherwise, the pressure of each of the above reactions is not critical. Generally, the reactions will be conducted at a pressure of about one to about three atmospheres, preferably at ambient pressure (about one atmosphere).
The compounds of the formula I which are basic in nature are capable of forming a wide variety of different salts with various inorganic and organic acids. Although such salts must be pharmaceutically acceptable for administration to animals, it is often desirable in practice to initially isolate a compound of the formula I from the reaction mixture as a pharmaceutically unacceptable salt and then simply convert the latter back to the free base compound by treatment with an alkaline reagent, and subsequently convert the free base to a pharmaceutically acceptable acid addition salt. The acid addition salts of the base compounds of this invention are readily prepared by treating the base compound with a substantially equivalent amount of the chosen mineral or organic acid in an aqueous solvent medium or in a suitable organic solvent such as methanol or ethanol. Upon careful evaporation of the solvent, the desired solid salt is obtained.
The acids which are used to prepare the pharmaceutically acceptable acid addition salts of the base compounds of this invention are those which form non-toxic acid addition salts, i.e., salts containing pharmacologically acceptable anions, such as hydrochloride, hydrobromide, hydroiodide, nitrate, sulfate or bisulfate, phosphate or acid phosphate, acetate, lactate, citrate or acid citrate, tartrate or bitartrate, succinate, maleate, fumarate, gluconate, saccharate, benzoate, methanesulfonate and pamoate [i.e., 1,1xe2x80x2-methylene-bis-(2-hydroxy-3-naphthoate)] salts.
Those compounds of the formula I which are also acidic in nature, are capable of forming base salts with various pharmacologically acceptable cations. Examples of such salts include the alkali metal or alkaline-earth metal salts and particularly, the sodium and potassium salts. These salts are all prepared by conventional techniques. The chemical bases which are used as reagents to prepare the pharmaceutically acceptable base salts of this invention are those which form non-toxic base salts with the herein described acidic compounds of formula I. These non-toxic base salts include those derived from such pharmacologically acceptable cations as sodium, potassium, calcium and magnesium, etc. These salts can easily be prepared by treating the corresponding acidic compounds with an aqueous solution containing the desired pharmacologically acceptable cations, and then evaporating the resulting solution to dryness, preferably under reduced pressure. Alternatively, they may also be prepared by mixing lower alkanolic solutions of the acidic compounds and the desired alkali metal alkoxide together, and then evaporating the resulting solution to dryness in the same manner as before. In either case, stoichiometric quantities of reagents are preferably employed in order to ensure completeness of reaction and maximum product yields.
Compounds of the formula I and their pharmaceutically acceptable salts (hereinafter also referred to, collectively, as xe2x80x9cthe active compoundsxe2x80x9d) are potent antagonists of the CCR1 receptors. The active compounds are useful in the treatment or prevention of autoimmune diseases (such as rheumatoid arthritis, type I diabetes (recent onset), inflammatory bowel disease, optic neuritis, psoriasis, multiple sclerosis, polymyalgia rheumatica, uveitis, and vasculitis), acute and chronic inflammatory conditions (such as osteoarthritis, adult respiratory distress syndrome, Respiratory Distress Syndrome of infancy, ischemia reperfusion injury, and glomerulonephritis), allergic conditions (such as asthma and atopic dermatitis), infection associated with inflammation (such as viral inflammation (including influenza and hepatitis) and Guillian-Barre), chronic bronchitis, xeno-transplantation, transplantation tissue rejection, atherosclerosis, restenosis, HIV infectivity (co-receptor usage), and granulomatous diseases (including sarcoidosis, leprosy and tuberculosis).
The activity of the compounds of the invention can be assessed according to procedures know to those of ordinary skill in the art. Examples of recognized methods for determining CCR1 induced migration can be found in Coligan, J. E., Kruisbeek, A. M., Margulies, D. H., Shevach, E. M., Strober, W. editors: Current Protocols In Immunology, 6.12.1-6.12.3. (John Wiley and Sons, NY, 1991). One specific example of how to determine the activity of a compound for inhibiting migration is described in detail below.
The ability of compounds to inhibit the chemotaxis to various chemokines can be evaluated using standard 48 or 96 well Boyden Chambers with a 5 micron polycarbonate filter. All reagents and cells can be prepared in standard RPMI (BioWhitikker Inc.) tissue culture medium supplemented with 1 mg/ml of bovine serum albumin. Briefly, MIP-1a (Peprotech, Inc., P.O. Box 275, Rocky Hill N.J.) or other test agonists, were placed into the lower chambers of the Boyden chamber. A polycarbonate filter was then applied and the upper chamber fastened. The amount of agonist chosen is that determined to give the maximal amount of chemotaxis in this system (e.g., 1 nM for MIP-1xcex1 should be adequate).
THP-1 cells (ATCC TIB-202), primary human monocytes, or primary lymphocytes, isolated by standard techniques can then be added to the upper chambers in triplicate together with various concentrations of the test compound. Compound dilutions can be prepared using standard serological techniques and are mixed with cells prior to adding to the chamber.
After a suitable incubation period at 37 degrees centigrade (e.g. 3.5 hours for THP-1 cells, 90 minutes for primary monocytes), the chamber is removed, the cells in the upper chamber aspirated, the upper part of the filter wiped and the number of cells migrating can be determined according to the following method.
For THP-1 cells, the chamber (a 96 well variety manufactured by Neuroprobe) can be centrifuged to push cells off the lower chamber and the number of cells can be quantitated against a standard curve by a color change of the dye fluorocein diacetate.
For primary human monocytes, or lymphocytes, the filter can be stained with Dif Quik(copyright) dye (American Scientific Products) and the number of cells migrating can be determined -microscopically.
The number of cells migrating in the presence of the compound are divided by the number of cells migrating in control wells (without the compound). The quotant is the % inhibition for the compound which can then be plotted using standard graphics techniques against the concentration of compound used. The 50% inhibition point is then determined using a line fit analysis for all concentrations tested. The line fit for all data points must have an coefficient of correlation (R squared) of  greater than 90% to be considered a valid assay.
All of the compounds of the invention that were tested had IC50 of less than 25 xcexcM, in the Chemotaxis assay.
The compositions of the present invention may be formulated in a conventional manner using one or more pharmaceutically acceptable carriers. Thus, the active compounds of the invention may be formulated for oral, buccal, intranasal, parenteral (e.g., intravenous, intramuscular or subcutaneous) or rectal administration or in a form suitable for administration by inhalation or insufflation. The active compounds of the invention may also be formulated for sustained delivery.
For oral administration, the pharmaceutical compositions may take the form of, for example, tablets or capsules prepared by conventional means with pharmaceutically acceptable excipients such as binding agents (e.g., pregelatinized maize starch, polyvinylpyrrolidone or hydroxypropyl methylcellulose); fillers (e.g., lactose, microcrystalline cellulose or calcium phosphate); lubricants (e.g., magnesium stearate, talc or silica); disintegrants (e.g., potato starch or sodium starch glycolate); or wetting agents (e.g., sodium lauryl sulphate). The tablets may be coated by methods well known in the art. Liquid preparations for oral administration may take the form of, for example, solutions, syrups or suspensions, or they may be presented as a dry product for constitution with water or other suitable vehicle before use. Such liquid preparations may be prepared by conventional means with pharmaceutically acceptable additives such as suspending agents (e.g., sorbitol syrup, methyl cellulose or hydrogenated edible fats); emulsifying agents (e.g., lecithin or acacia); non-aqueous vehicles (e.g., almond oil, oily esters or ethyl alcohol); and preservatives (e.g., methyl or propyl p-hydroxybenzoates or sorbic acid).
For buccal administration, the composition may take the form of tablets or lozenges formulated in conventional manner.
The active compounds of the invention may be formulated for parenteral administration by injection, including using conventional catheterization techniques or infusion. Formulations for injection may be presented in unit dosage form, e.g., in ampules or in multi-dose containers, with an added preservative. The compositions may take such forms as suspensions, solutions or emulsions in oily or aqueous vehicles, and may contain formulating agents such as suspending, stabilizing and/or dispersing agents. Alternatively, the active ingredient may be in powder form for reconstitution with a suitable vehicle, e.g., sterile pyrogen-free water, before use.
The active compounds of the invention may also be formulated in rectal compositions such as suppositories or retention enemas, e.g., containing conventional suppository bases such as cocoa butter or other glycerides.
For intranasal administration or administration by inhalation, the active compounds of the invention are conveniently delivered in the form of a solution or suspension from a pump spray container that is squeezed or pumped by the patient or as an aerosol spray presentation from a pressurized container or a nebulizer, with the use of a suitable propellant, e.g., dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas. In the case of a pressurized aerosol, the dosage unit may be determined by providing a valve to deliver a metered amount. The pressurized container or nebulizer may contain a solution or suspension of the active compound. Capsules and cartridges (made, for example, from gelatin) for use in an inhaler or insufflator may be formulated containing a powder mix of a compound of the invention and a suitable powder base such as lactose or starch.
A proposed dose of the active compounds of the invention for oral, parenteral or buccal administration to the average adult human for the treatment of the conditions referred to above (e.g., rheumatoid arthritis) is 0.1 to 1000 mg of the active ingredient per unit dose which could be administered, for example, 1 to 4 times per day.
Aerosol formulations for treatment of the conditions referred to above (e.g., rheumatoid arthritis) in the average adult human are preferably arranged so that each metered dose or xe2x80x9cpuffxe2x80x9d of aerosol contains 20 xcexcg to 1000 xcexcg of the compound of the invention. The overall daily dose with an aerosol will be within the range 0.1 mg to 1000 mg. Administration may be several times daily, for example 2, 3, 4 or 8 times, giving for example, 1, 2 or 3 doses each time.
The active agents can be formulated for sustained delivery according to methods well known to those of ordinary skill in the art. Examples of such formulations can be found in U.S. Pat. Nos. 3,538,214, 4,060,598, 4,173,626, 3,119,742, and 3,492,397.
The compounds of the invention can also be utilized in combination therapy with other therapeutic agents such as with T-cell immunosuppressant agents such as cyclosporin A and FK-506, with steroid sparing agents such as Cellcept(copyright), or with classical anti-inflammatory agents (e.g. cyclooxygenase/lipoxegenase inhibitors) such as tenidap, aspirin, acetaminophen, naproxen and piroxicam.
The following Examples illustrate the preparation of the compounds of the present invention. Melting points are uncorrected. NMR data are reported in parts per million (xcex4) and are referenced to the deuterium lock signal from the sample solvent (deuteriochloroform unless otherwise specified). Commercial reagents were utilized without further purification. THF refers to tetrahydrofuran. DMF refers to N,N-dimethylformamide. Chromatography refers to column chromatography performed using 32-63 mm silica gel and executed under nitrogen pressure (flash chromatography) conditions. Low Resolution Mass Spectra (LRMS) were recorded on either a Hewlett Packard 5989(copyright), utilizing chemical ionization (ammonium), or a Fisons (or Micro Mass) Atmospheric Pressure Chemical Ionization (APCI) platform which uses a 50/50 mixture of acetonitrile/water with 0.1% formic acid as the ionizing agent. Room or ambient temperature refers to 20-25xc2x0 C. All non-aqueous reactions were run under a nitrogen atmosphere for convenience and to maximize yields. Concentration at reduced pressure means that a rotary evaporator was used. The names for the compounds of the invention were created by the Autonom 2.0 PC-batch version from Beilstein Informationssysteme GmbH (ISBN 3-89536-976-4).